STIM1 is essential for Fcgamma receptor activation and autoimmune inflammation.
Fcgamma receptors (FcgammaRs) on mononuclear phagocytes trigger autoantibody and immune complex-induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRgamma-based activation is critical in the pathogenesis of these diseases, although the contribution of FcgammaR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum-resident calcium sensor, STIM1, cannot activate FcgammaR-induced Ca(2+) entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcgammaR activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunologic diseases.
Braun
Attila
A
Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
Gessner
J Engelbert
JE
Varga-Szabo
David
D
Syed
Shahzad N
SN
Konrad
Stephanie
S
Stegner
David
D
Vögtle
Timo
T
Schmidt
Reinhold E
RE
Nieswandt
Bernhard
B
D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002118:Calcium / Q000276:immunology; D015220:Calcium Channels; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071737:Stromal Interaction Molecule 1
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D015220:Calcium Channels; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium